There is a large body of evidence suggesting that important relationships exist between retinoids and cancer. Both a therapeutic and preventive role for retinoids have been indicated by a variety of research. To investigate the role of retinoids in various carcinogenic processes we have begun a series of retinoid turnover studies using rats, to investigate the effects of supplementation of diets either low or normal in vitamin A content with synthetic retinoids (either 4-HPR or all-trans retinoic acid). As expected, based on work from other laboratories, there was a decline in plasma retinol in rats fed these synthetic retinoids. We are now in the process of carrying out in vivo tracer kinetics studies of retinol metabolism to examine how these changes in plasma retinol affect plasma and tissue retinol kinetics. Following IV injection of radiolabelled retinol associated with its normal plasma transport protein, retinol-binding protein, samples of plasma, a variety of tissues, urine, and feces are collected over time periods ranging from 15 minutes to 40 days. Labelled and unlabelled vitamin A compounds will be characterized and quantitated. Using physiologically based computer modelling and multi compartmental analysis techniques, we will develop mathematical models of vitamin A metabolism. These models will provide both quantitative and descriptive information concerning the movement of retinoids of interest among the various tissues, the uptake and utilization of retinoids by these tissues, and the effects of synthetic retinoids on vitamin A metabolism in individual tissues as well as in the whole body.